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CLINICAL RESEARCH: MYOCARDIAL ISCHEMIA AND INFARCTION

Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome

^* Department of Medicine, Montreal Heart Institute, and University of Montreal, Montreal, Quebec, Canada

Manuscript received July 7, 2003; revised manuscript received October 15, 2003, accepted October 20, 2003.

^* Reprint requests and correspondence: Dr. Pierre Théroux, Montreal Heart Institute, 5000 Belanger East, Montreal, Quebec, Canada H1T 1C8.
pierre.theroux{at}icm-mhi.org

OBJECTIVES: We sought to characterize the effects of clopidogrel on the activation of circulating platelets, the activation and aggregation of ex vivo platelets, and the interactions with leukocytes in patients with a non–ST-segment elevation in acute coronary syndromes (ACS).

BACKGROUND: The significant benefits of clopidogrel in cardiovascular trials suggest that blockage of the P2Y₁₂ receptor may be associated with important biologic consequences.

METHODS: Blood samples obtained from 23 ACS patients before and 24 h after a loading dose of clopidogrel (300 mg) were analyzed by whole-blood flow cytometry, light transmission aggregometry in platelet-rich plasma, and plasma enzyme-linked immunoassays. A thrombin receptor agonist peptide (TRAP) and adenosine diphosphate (ADP) were used as agonists. Normal individuals pretreated with aspirin served as controls.

RESULTS: Clopidogrel attenuated platelet aggregation to both ADP (10 µmol/l) and TRAP (10 µmol/l) by 22% and P-selectin expression by 16% and 25%, respectively. The drug decreased the excess platelet-monocyte and platelet-neutrophil conjugates found in the blood of ACS patients (p < 0.01) and prevented their formation ex vivo with agonist stimulation. Plasma levels of soluble CD40L were reduced by 27% (p < 0.001) and of soluble P-selectin by 15% (p < 0.001).

CONCLUSIONS: Clopidogrel attenuates the agonist effects of ADP and TRAP on platelet secretion, aggregation, and formation of platelet-monocyte and platelet-neutrophil conjugates in patients with ACS. These effects may all contribute to the clinical benefits of the drug in these syndromes.

Abbreviations and Acronyms   ACS = acute coronary syndrome   ADP = adenosine diphosphate   FITC = fluorescein isothiocyanate   Ig = immunoglobulin   PAR = protease-activated receptor   PMN = polymorphonuclear cell   PPP = platelet-poor plasma   PRP = platelet-rich plasma   TRAP = thrombin receptor agonist peptide

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